Diabetes is increasingly recognized to be influenced by complex genetic and metabolic factors involving[unreadable] multiple organs and molecules. A single important molecule may directly or indirectly control the function of[unreadable] other molecules and multiple tissues. The function of an adult tissue is clearly dependent upon its history,[unreadable] i.e., its differentiation and development, as well as upon signals emanating from other tissues and the[unreadable] environment. This Program Project Grant involves five outstanding investigators, each focused on a specific[unreadable] molecule that regulates development and metabolic function of a specific tissue. Project 1 (Lazar)[unreadable] addresses the role of resistin, a novel adipocyte-secreted factor (adipokine), in insulin resistance and[unreadable] atherosclerosis. Project 2 (Ahima) examines the role of the central nervous system in mediating the[unreadable] metabolic effects of adipokines, focusing on adiponectin, leptin, and resistin. Project 3 (Birnbaum)[unreadable] investigates the regulation of metabolism by Akt/PKB in beta cell and the brain. Project 4 (Kaestner)[unreadable] addresses the role of the Foxa family of transcription factors, as well as coactivators, in liver metabolism.[unreadable] Project 5 (Staffers) focuses on regulation of pancreatic development and differentiation by the[unreadable] homeodomain transcription factor PDX. Each individual project addresses an important hypothesis using[unreadable] molecular and genetic tools, including in vivo mutational analysis. A particularly exciting aspect of this[unreadable] proposal is its tremendous potential for synergism. Frequent interactions will maximize the opportunities for[unreadable] new discoveries related to obvious or surprising interactions between this variety of molecules and metabolic[unreadable] tissues. These interactions will be facilitated by a collaborative environment at the University of[unreadable] Pennsylvania; the close physical proximity of the investigators; an administrative core that coordinates[unreadable] frequent meetings among the investigators and with scientific visitors; an outstanding morphology core in a[unreadable] dedicated central space that encourages physical and intellectual interactions via the technical director and[unreadable] shared personnel; and embryonic stem cell core and metabolic phenotyping cores that facilitate interactions[unreadable] and rapid dissemination of new results, techniques, and ideas. The proposed studies will address major and[unreadable] specific questions relevant to diabetes and metabolic diseases. At the same time, the specific investigators,[unreadable] environment, and format of this proposal facilitate interactions that should enhance the discovery process.[unreadable] There is an excellent likelihood that advances made by this program project group will have a positive impact[unreadable] on the epidemics of diabetes and metabolic diseases that are ravaging our society.[unreadable]